Traumatic brain injury (TBI) is a major cause of disability wartime and civilian trauma. Current clinical assessments and imaging cannot always reliably determine the presence and severity of injury. We propose to use two advanced MRI methods- diffusion tensor imaging (DTI), and resting-state fMRI correlation analysis- to address these issues. This approach is based on the hypothesis that traumatic axonal injury is a principal cause of impaired brain function following TBI. We have found that DTI accurately and quantitatively detects axonal injury in areas where conventional MRI appears normal. Resting-state fMRI correlation analysis may complementarily allow assessment of the functional consequences of axonal injury. Our initial imaging experience in human TBI patients has already provided remarkable insights. We plan to conduct a pilot study of 50 chronic TBI patients with well-characterized neurological and neuropsychological deficits and scan them with DTI and resting-state functional MRI. We propose 3 aims, designed to test the hypothesis that traumatic axonal injury is a principal cause of impaired brain function following TBI, refine the methods, and establish the clinical utility of this advanced MRI methods. Specific Aim 1: To assess whether abnormalities observed with these imaging methods in brain regions known to be necessary for specific neurological functions (e.g. motor, sensory, language, short-term memory) correlate with deficits defined by previously documented neurological and neuropsychological testing. Comparison to conventional MRI findings in the same regions will be made. Specific Aim 2: To use these advanced imaging techniques to help localize injuries associated with common sequelae of traumatic brain injury such as attention deficit disorder whose anatomical substrates are currently not entirely known. Specific Aim 3: To determine whether the total burden of functionally significant axonal injury as reflected by DTI and resting-state fMRI correlation analysis more accurately reflects overall clinical outcome than lesion burden detected by conventional MRI methods If successful, this approach could dramatically enhance therapeutic development and management of TBI patients reducing the burden of this neurological disorder, a key mission of NNDS. Long term, it is the hope of this project to apply these techniques to other understudied neurological conditions. PUBLIC HEALTH RELEVANCE: Accurate diagnostics like DTI and resting-state fMRI could improve triage, stratification for clinical trials, rehabilitation and life-planning, substantially impacting public health.